A major unmet goal of drug abuse research is to understand the neural substrates of reinforcement of drugs of abuse in humans and the role that these mechanisms may play in initiating and sustaining drug dependence. This proposal for a Program Project is a renewal of our currently funded PO1 from the National Institute on Drug Abuse, "fMRI of Cocaine Action". The overall goal of this program continues to be the utilization and refinement of state of the art techniques to produce interpretable brain maps, functional anatomy of human subjective states that occur in response to c0caine, with particular emphasis during the funding cycle on the braid reward circuitry mediating cocaine response in humans, using functional magnetic resonance imaging (fMRI) as the principal tool. To effectively perform the experiments to test these hypotheses, three Projects and three Cores. As in our current funding cycle, Project 1 is an fMRI study of regional brain activation by cocaine in cocaine-dependent human subjects. The objective of Project 1 is to investigate of brain reward circuitry in mediating the cocaine response in humans, and to distinguish euphoria-like brain activation from craving-like brain activation. Project 2 has evolved to begin the important work of developing rodent models to more completely understand pharmacologically mediated MRI signal changes observed after administration of dopamine ligands. The studies proposed in Project 2 are of fundamental importance for understanding and interpreting functional imaging data following cocaine administration in animals and humans. Project 3 utilizes rodent models, including both drug-naive and cocaine- dependent rats and, new to this funding cycle, knockout mice, to address specific pharmacological and drug dependence issues which cannot be readily addressed in humans. We anticipate that results from these experiments, will identify the role of particular neurotransmitter mechanisms (namely, dopaminergic and serotonergic) that underlie the pattern of cocaine-induced brain activation. The hypothesis driven experiments using state of the art functional imaging techniques that we proposed in Project 1, in concert with experiments proposed in Project 2 focused on identifying mechanisms coupling psychostimulant administration to cerebrovascular response, are designed to provide a deeper understanding of the mechanism of cocaine action. The Program Project mechanism is ideal for a multi-disciplinary project with these goals in mind. We anticipate that the experiments in rodents will advance our understanding of acute and chronic effects of cocaine on brain function, facilitating interpretation of data from Project 1, thereby providing a crucial effects of cocaine on brain function, facilitating interpretation of data from Project, thereby providing a crucial link in understanding the fMRI correlates and neurobiology consequences of cocaine addiction in humans.